Bortezomib Reverses Antibody-Mediated Transplant Rejection

Daniel M. Keller, PhD

May 23, 2011

May 23, 2011 (Philadelphia, Pennsylvania) — In a report of 96 episodes of antibody-mediated rejection (AMR) occurring in 81 recipients of kidney transplants, the proteasome inhibitor bortezomib effectively reversed AMR and was associated with graft survival and histologic improvement in most patients, E. Steve Woodle, MD, professor and chairman of surgery and chief of the Division of Transplant Surgery at the University of Cincinnati in Ohio, told the American Transplant Congress 2011.

AMR has been recognized within the past decade as an important contributor to acute and chronic rejection and graft loss. It typically does not respond to antirejection therapies aimed against T-cell–mediated immunity.

Forty-five medical centers agreed to share data after adopting a standardized protocol consisting of a single dose of rituximab, 375 mg/m2, on day 1, followed by 4 doses of bortezomib, 1.3 mg/m2, on days 1, 4, 7, and 10, preceded each time by plasmapheresis, with further plasmapheresis on days 14, 16, and 18. These latter pheresis procedures were performed to remove existing antibodies and allow quantification of antibody production from residual B-cell clones. The immunodominant anti-HLA antibodies directed against donor-specific antigens were identified. Thirteen centers contributed data to the current report.

African Americans comprised 42% of the cohort, and 21% of all patients were noncompliant. "Patient survival has been excellent, to date almost 99%," Dr. Woodle said. "The time post transplant to rejection was a median of 11.9 months, a mean of 30 months, with a range from early on to patients 10 years out or more." The follow-up time was 8 to 9 months median or mean.

About one-third of patients experienced early AMR and the rest late AMR after transplantation, averaging about 5 years out for his institution and 2.5 to 3 years out at collaborating centers. Most of the immunodominant donor-specific antibodies (iDSAs) were about equally divided against Class I or Class II major histocompatibility complex antigens in early rejection but were predominantly directed against Class II antigens in late AMR, especially against DQ specificities (76% against DQ at his center and 59% at the collaborating centers).

During early rejection, about 90% of patients underwent kidney biopsies at the (originating) Cincinnati center for histologic analysis, and about three-quarters underwent biopsies at the collaborating centers. "About 70% of those that were biopsied were improved," Dr. Woodle said. Histologic improvement during late AMR was slightly lower than during the early episodes.

Graft survival was about 80% to 90% in early AMR and 67% to 76% in late AMR. Patient survival has been 100% for early AMR and 74% to 76% for late episodes. Use of the treatment protocol was associated with a maximum reduction in iDSAs of 76% at the originating center and 54% at the collaborating centers during early AMR. Significant improvements also occurred during late AMR.

Serum creatinine levels improved more after treatment for early AMR than they did when patients were treated during late AMR episodes. "Late rejection creatinines are higher in general as one might expect, and they don't show improvement to baseline," Dr. Woodle said. "They wind up around 2 mg/dL rather than 1.2-1.5 [mg/dL]."

He said peripheral neuropathy is probably the most exposure-limiting adverse effect with bortezomib. In the study, only about 2% to 3% of patients experienced painful neuropathy requiring narcotics (grade 3), a rate similar to that seen when the drug is used in the oncology setting.

No malignant tumors occurred in the study. Some viral infections occurred early on, which responded to antiviral therapy and reduction in immunosuppressive drugs. During late AMR, the rate of opportunistic infections was lower at about 3% to 4%. No deaths occurred related to opportunistic infections.

"In conclusion, results with proteasome inhibitor therapy differ between early and late antibody-mediated rejection. Results at the originating center were similar to those at collaborative sites," Dr. Woodle said. "Patient survival has been excellent. Overall graft survival is comparable or higher than reports with other therapies.

"Graft survival is lower with a late AMR. This is typical of what's been reported with IVIG [intravenous immunoglobulin] and other types of therapies. The toxicities are acceptable, and the opportunistic infection and malignancy rates are also acceptable," he concluded. Compared with use of bortezomib in the oncology setting to treat multiple myeloma, he said, drug exposure in the transplant patients was relatively low.

"I think the take-home message with the proteasome inhibitors and plasma cell targeted therapy is that these are biologically targeted therapies," Dr. Woodle told Medscape Medical News. "They're fundamentally different than IVIG, where the primary mechanism of action is not known or is not well sorted out." He expects to see many drugs coming out over the next several years that will target the humoral immune response and compares today to the era of the development of T-cell–directed therapies 25 years ago. With a knowledge of mechanisms, he predicts that drugs may be used in combination to target plasma cells to treat AMR.

He explained that AMR affects all solid organ transplants. "If you look at the reasons why people lose their grafts, there's evidence to suggest that the predominant mechanism is antibody mediated," he said.

Early AMR may be more amenable to treatment with a proteasome inhibitor because there are probably no memory B cells and plasma cells will just be differentiating from B cells, he observed. Late AMR involves memory B cells, and plasma cells are well established.

Session moderator Tomasz Kozlowski, MD, assistant professor of surgery at the University of North Carolina at Chapel Hill and not a participant in the study, agreed, telling Medscape Medical News, "Early acute rejection is much easier to control and address. Delayed antibody-mediated rejection that is switching into the chronic state is much more difficult to reverse, and the damage is already done and can be somewhat stopped but not reversed."

He commented that the protocol used in the study "is very exciting," and he expects to see results from this group showing "which component of this protocol is really contributing to the success and how we actually define the success."

Knowing what to measure in AMR is critical, Dr. Kozlowski said. "The question would be how we define success in desensitization and how we define success in transplanting kidneys for patients that are highly sensitized or have donor-specific antibodies. We don't have criteria."

Dr. Woodle has disclosed no relevant financial relationships except that he discussed off-label use of bortezomib. Dr. Kozlowski has disclosed no relevant financial relationships.

American Transplant Congress (ATC) 2011: Abstract 429. Presented May 4, 2011.

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